Sirtuin 1 Modulates Cellular Responses to Hypoxia by Deacetylating Hypoxia-Inducible Factor 1α

SummaryTo survive in hypoxic environments, organisms must be able to cope with redox imbalance and oxygen deficiency. The SIRT1 deacetylase and the HIF-1α transcription factor act as redox and oxygen sensors, respectively. Here, we found that SIRT1 binds to HIF-1α and deacetylates it at Lys674, which is acetylated by PCAF. By doing so, SIRT1 inactivated HIF-1α by blocking p300 recruitment and consequently repressed HIF-1 target genes. During hypoxia, SIRT1 was downregulated due to decreased NAD+ levels, which allowed the acetylation and activation of HIF-1α. Conversely, when the redox change was attenuated by blocking glycolysis, SIRT1 was upregulated, leading to the deacetylation and inactivation of HIF-1α even in hypoxia. In addition, we confirmed the SIRT1-HIF-1α interaction in hypoxic mouse tissues and observed in vivo that SIRT1 has negative effects on tumor growth and angiogenesis. Our results suggest that crosstalk between oxygen- and redox-responsive signal transducers occurs through the SIRT1-HIF-1α interaction.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (136 K)Download as PowerPoint slideHighlights► PCAF acetylates Lys674 of HIF-1α, which is reversed by SIRT1 deacetylase ► SIRT1 inactivates HIF-1 signaling by blocking p300 recruitment by HIF-1α ► During hypoxia, SIRT1 is suppressed redox dependently, which ensures HIF-1 signaling ► SIRT1 interacts with HIF-1α in hypoxic normal tissues and in tumor xenografts